4DJW

Structure of BACE Bound to 2-imino-3-methyl-5-phenyl-5-(3-(pyridin-3-yl)phenyl)imidazolidin-4-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor.

Cumming, J.N.Smith, E.M.Wang, L.Misiaszek, J.Durkin, J.Pan, J.Iserloh, U.Wu, Y.Zhu, Z.Strickland, C.Voigt, J.Chen, X.Kennedy, M.E.Kuvelkar, R.Hyde, L.A.Cox, K.Favreau, L.Czarniecki, M.F.Greenlee, W.J.McKittrick, B.A.Parker, E.M.Stamford, A.W.

(2012) Bioorg Med Chem Lett 22: 2444-2449

  • DOI: https://doi.org/10.1016/j.bmcl.2012.02.013
  • Primary Citation of Related Structures:  
    4DJU, 4DJV, 4DJW, 4DJX, 4DJY

  • PubMed Abstract: 

    From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.


  • Organizational Affiliation

    Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. jared.cumming@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
414Homo sapiensMutation(s): 0 
Gene Names: BACEBACE1KIAA1149
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
0KP Binding MOAD:  4DJW Ki: 530 (nM) from 1 assay(s)
BindingDB:  4DJW Ki: 110 (nM) from 1 assay(s)
IC50: min: 630, max: 1680 (nM) from 2 assay(s)
PDBBind:  4DJW Ki: 530 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.55α = 90
b = 89.639β = 90
c = 131.013γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-03-21
    Type: Initial release
  • Version 1.1: 2012-04-04
    Changes: Database references